1. Field of the Invention
The present invention relates to peptides having activities of transforming growth factor-beta (TGF-β) and their uses.
2. Description of the Related Art
Transforming growth factor-beta (TGF-β) is a group of polypeptide growth factors regulating cell differentiation and growth. This group also includes Mulleria inhibitors (Cate et al, Cell, 45: 685-698 (1986)), inhibins (Mason et al., Nature, 318: 659-663 (1985)), and proteins derived from transcripts of DPP-C (decapentaplegic gene complex) in Drosophila (Padgett et al., Nature, 325: 81-84 (1987)). TGF-β consists of two similar disulfide-linked subunits each having a molecular weight of 13,000 daltons (Assoian et al, J. Biol. Chem., 258: 7155-7160 (1983); Frolik et al, Proc. Natl. Acad. Sci. USA, 80: 3676-3680 (1983); Frolik et al., J. Biol. Chem. 260: 10995-11000 (1984)). TGF-βs have been purified from several tissues, including placenta (Frolik et al., Nature, 325: 81-84 (1983)), human platelet (Childs et al, Proc. Natl. Acad. Sci. USA, 79: 5312-5316 (1982); Assioan et al., J. Biol. Chem., 258: 7155-7160 (1983)), kidney (Roberts et al., Biochemistry, 22: 5692-5698 (1983)), and bovine demineralized bone (Seyedin et al., Proc. Natl. Acad. Sci. USA, 82: 119-123 (1985)). TGF-β is able to increase anchorage-independent growth of normal rat kidney fibroblast in the presence of 10% serum and epidermal growth factors (Roberts et al, Proc. Natl. Acad. Sci. USA, 78: 5339-5343 (1981); Roberts et al., Nature, 295: 417-419 (1982); Twardzik et al, J. Cell Biochem., 28: 289-297 (1985)), and to induce colonization of AKR-2B fibroblasts in only 10% serum (Tucker et al., Cancer Res., 43: 1518-1586 (1983)). In addition, it has been reported that TGF-β may cause differentiation of muscle mesenchymal cells and generation of cartilage-specific macromolecules in fetal rats (Seyedin et al., J. Biol. Chem., 261: 5693-5695 (1986)).
In contrast to various effects on cell proliferation, it has been observed that not only functional proteins having similar activities of TGF-β isolated from African green monkey kidney epithelial cells (BSC-1) but TGF-β purified from human platelet could inhibit the growth of certain cells during cell culture (Tucker et al., Science, 226: 705-707 (1984)). TGF-β was also found to inhibit the growth of a few human tumor cells (Roberts et al., Proc. Natl. Acad. Sci. USA, 82: 119-123 (1985)). These inhibitory or stimulatory effects of TGF-β have been reported to be dependent on several factors related to cell morphology and cell physiological conditions (Spon et al., Science, 232: 534 (1986)).
TGF-β cDNA clones were isolated from human (Derynck et al, Nature, 316: 701-705 (1985)), mouse (Derynck et al., J. Biol. Chem., 261: 4377-4379 (1986)), and simian virus 40 (Sharples et al., DNA, 6: 239-244 (1987)). By analyzing their DNA sequences, it was reported that TGF-β is synthesized as a large precursor polypeptide and then spliced to produce a TGF-β monomer. The amino acid sequence between aforementioned TGF-β precursor proteins was found to have much higher homology.
Recently, it has been identified that a protein isolated from bovine demineralized bone is related to TGF-β (Seyedin et al., J. Biol. Chem, 262: 1946-1949 (1987)). The protein has also been isolated from other species including porcine blood platelets (Cheifetz et al., Cell, 48: 409-415 (1987)), human prostatic adenocarcinoma cell line PC-3 (Ikeda et al., Biochemistry, 26: 2406-2410 (1987)), and human glioblast cell (Wrann et al., EMBO J, 6: 1633-1636 (1987)). Since the amino acid sequence of this protein is partially homologous to that of TGF-β, it was named as TGF-β2. Thus, the TGF-βs isolated from human (Derynck et al., Nature, 316: 701-705 (1985)), mouse (Derynck et al., J. Biol. Chem., 261: 4377-4379 (1986)), and simian virus 40 (Sharples et. al., DNA, 6: 239-244 (1987)) were renamed as TGF-β1.
Throughout this application, various patents and publications are referenced, and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.